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Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting.

Lipson EJ, Sharfman WH, Chen S, McMiller TL, Pritchard TS, Salas JT, Sartorius-Mergenthaler S, Freed I, Ravi S, Wang H, Luber B, Sproul JD, Taube JM, Pardoll DM, Topalian SL - J Transl Med (2015)

Bottom Line: Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002).Cyclophosphamide did not affect numbers of circulating Tregs.NCT01435499.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, 1550 Orleans Street, Room 507, Baltimore, MD, 21287, USA. evanlipson@jhmi.edu.

ABSTRACT

Background: Limited adjuvant treatment options exist for patients with high-risk surgically resected melanoma. This first-in-human study investigated the safety, tolerability and immunologic correlates of Melanoma GVAX, a lethally irradiated granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting.

Methods: Patients with stage IIB-IV melanoma were enrolled following complete surgical resection. Melanoma GVAX was administered intradermally once every 28 days for four cycles, at 5E7 cells/cycle (n = 3), 2E8 cells/cycle (n = 9), or 2E8 cells/cycle preceded by cyclophosphamide 200 mg/m(2) to deplete T regulatory cells (Tregs; n = 8). Blood was collected before each vaccination and at 4 and 6 months after treatment initiation for immunologic studies. Vaccine injection site biopsies and additional blood samples were obtained 2 days after the 1st and 4th vaccines.

Results: Among 20 treated patients, 18 completed 4 vaccinations. Minimal treatment-related toxicity was observed. One patient developed vitiligo and patches of white hair during the treatment and follow-up period. Vaccine site biopsies demonstrated complex inflammatory infiltrates, including significant increases in eosinophils and PD-1+ lymphocytes from cycle 1 to cycle 4 (P < 0.05). Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002). Cyclophosphamide did not affect numbers of circulating Tregs. No significant changes in anti-melanoma immunity were observed in peripheral T cells by interferon-gamma ELIPSOT, or immunoglobulins by serum Western blotting.

Conclusion: Melanoma GVAX was safe and tolerable in the adjuvant setting. Pharmacodynamic testing revealed complex vaccine site immune infiltrates and an immune-reactive profile in circulating monocytic cell subsets. These findings support the optimization of Melanoma GVAX with additional monocyte and dendritic cell activators, and the potential development of combinatorial treatment regimens with synergistic agents.

Trial registration: NCT01435499.

No MeSH data available.


Related in: MedlinePlus

Vaccine site biopsy reveals a mixed inflammatory infiltrate. Representative photomicrograph of a skin punch biopsy obtained from a patient in Cohort A, 2 days after receiving the first dose of Melanoma GVAX. H&E staining reveals a dense, mixed inflammatory infiltrate centered primarily in the superficial subcutaneous adipose tissue (blue inset box), including lymphocytes, histiocytes, eosinophils, and irradiated melanoma vaccine cells. Left image, ×10 original magnification; right image, ×200 original magnification. Black arrowhead, dermal/subcutaneous junction; black arrows, Melanoma GVAX cells; green arrows, eosinophils. Immunohistochemical characterization is shown in Additional file 3: Figure S2.
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Fig2: Vaccine site biopsy reveals a mixed inflammatory infiltrate. Representative photomicrograph of a skin punch biopsy obtained from a patient in Cohort A, 2 days after receiving the first dose of Melanoma GVAX. H&E staining reveals a dense, mixed inflammatory infiltrate centered primarily in the superficial subcutaneous adipose tissue (blue inset box), including lymphocytes, histiocytes, eosinophils, and irradiated melanoma vaccine cells. Left image, ×10 original magnification; right image, ×200 original magnification. Black arrowhead, dermal/subcutaneous junction; black arrows, Melanoma GVAX cells; green arrows, eosinophils. Immunohistochemical characterization is shown in Additional file 3: Figure S2.

Mentions: Vaccine site biopsy specimens taken 2 days after both Cycle 1 and Cycle 4 vaccinations were available from 16 patients for CD3, CD4, CD8, CD20, and CD68 IHC. Because of limited material, H&E staining was performed on only 13 paired specimens, CD1a staining on 15, PD-1 and HMB-45 on 12, and FoxP3 on 8 paired specimens. A representative vaccine site biopsy is shown in Figure 2, and representative IHC stains are shown in Additional file 3: Figure S2, revealing selective infiltration of macrophages and eosinophils at vaccine sites. This is consistent with the local biological effects of GM-CSF secretion by Melanoma GVAX.Figure 2


Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting.

Lipson EJ, Sharfman WH, Chen S, McMiller TL, Pritchard TS, Salas JT, Sartorius-Mergenthaler S, Freed I, Ravi S, Wang H, Luber B, Sproul JD, Taube JM, Pardoll DM, Topalian SL - J Transl Med (2015)

Vaccine site biopsy reveals a mixed inflammatory infiltrate. Representative photomicrograph of a skin punch biopsy obtained from a patient in Cohort A, 2 days after receiving the first dose of Melanoma GVAX. H&E staining reveals a dense, mixed inflammatory infiltrate centered primarily in the superficial subcutaneous adipose tissue (blue inset box), including lymphocytes, histiocytes, eosinophils, and irradiated melanoma vaccine cells. Left image, ×10 original magnification; right image, ×200 original magnification. Black arrowhead, dermal/subcutaneous junction; black arrows, Melanoma GVAX cells; green arrows, eosinophils. Immunohistochemical characterization is shown in Additional file 3: Figure S2.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4491237&req=5

Fig2: Vaccine site biopsy reveals a mixed inflammatory infiltrate. Representative photomicrograph of a skin punch biopsy obtained from a patient in Cohort A, 2 days after receiving the first dose of Melanoma GVAX. H&E staining reveals a dense, mixed inflammatory infiltrate centered primarily in the superficial subcutaneous adipose tissue (blue inset box), including lymphocytes, histiocytes, eosinophils, and irradiated melanoma vaccine cells. Left image, ×10 original magnification; right image, ×200 original magnification. Black arrowhead, dermal/subcutaneous junction; black arrows, Melanoma GVAX cells; green arrows, eosinophils. Immunohistochemical characterization is shown in Additional file 3: Figure S2.
Mentions: Vaccine site biopsy specimens taken 2 days after both Cycle 1 and Cycle 4 vaccinations were available from 16 patients for CD3, CD4, CD8, CD20, and CD68 IHC. Because of limited material, H&E staining was performed on only 13 paired specimens, CD1a staining on 15, PD-1 and HMB-45 on 12, and FoxP3 on 8 paired specimens. A representative vaccine site biopsy is shown in Figure 2, and representative IHC stains are shown in Additional file 3: Figure S2, revealing selective infiltration of macrophages and eosinophils at vaccine sites. This is consistent with the local biological effects of GM-CSF secretion by Melanoma GVAX.Figure 2

Bottom Line: Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002).Cyclophosphamide did not affect numbers of circulating Tregs.NCT01435499.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, 1550 Orleans Street, Room 507, Baltimore, MD, 21287, USA. evanlipson@jhmi.edu.

ABSTRACT

Background: Limited adjuvant treatment options exist for patients with high-risk surgically resected melanoma. This first-in-human study investigated the safety, tolerability and immunologic correlates of Melanoma GVAX, a lethally irradiated granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting.

Methods: Patients with stage IIB-IV melanoma were enrolled following complete surgical resection. Melanoma GVAX was administered intradermally once every 28 days for four cycles, at 5E7 cells/cycle (n = 3), 2E8 cells/cycle (n = 9), or 2E8 cells/cycle preceded by cyclophosphamide 200 mg/m(2) to deplete T regulatory cells (Tregs; n = 8). Blood was collected before each vaccination and at 4 and 6 months after treatment initiation for immunologic studies. Vaccine injection site biopsies and additional blood samples were obtained 2 days after the 1st and 4th vaccines.

Results: Among 20 treated patients, 18 completed 4 vaccinations. Minimal treatment-related toxicity was observed. One patient developed vitiligo and patches of white hair during the treatment and follow-up period. Vaccine site biopsies demonstrated complex inflammatory infiltrates, including significant increases in eosinophils and PD-1+ lymphocytes from cycle 1 to cycle 4 (P < 0.05). Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002). Cyclophosphamide did not affect numbers of circulating Tregs. No significant changes in anti-melanoma immunity were observed in peripheral T cells by interferon-gamma ELIPSOT, or immunoglobulins by serum Western blotting.

Conclusion: Melanoma GVAX was safe and tolerable in the adjuvant setting. Pharmacodynamic testing revealed complex vaccine site immune infiltrates and an immune-reactive profile in circulating monocytic cell subsets. These findings support the optimization of Melanoma GVAX with additional monocyte and dendritic cell activators, and the potential development of combinatorial treatment regimens with synergistic agents.

Trial registration: NCT01435499.

No MeSH data available.


Related in: MedlinePlus